EU-GMP 附录一 翻译搞.doc

ANNEX 1 附件1MANUFACTURE OF STERILE MEDICINAL PRODUCTS无菌医药产品的生产Principle 原则The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.无菌药品的生产，必须符合一些特殊的要求，以防止微生物、微粒和热源的污染。

这很大程度上要依赖工作人员的技术水平、培训和工作态度在这方面质量保证显得特别重要，这种类型的生产，必须严格按照完善的和经过验证的生产方法和工作程序仅靠产品的最终灭菌和某一方面的质量控制是不允许的Note:This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards.注：本规范没有详述测定空气、表面等微生物和微粒洁净度的详细方法，请参阅EN/ISO中相关标准General 一般要求1. The manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.无菌产品的生产要在洁净区域内进行，进入这些区域内的人员、设备或原料，必须通过气闸室。

洁净区必须保持一定的洁净级别，空气必须通过规定的过滤器2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages.各种原料的准备、产品的准备和灌装，必须在洁净区的不同区域进行，生产操作分为两类，一是最终灭菌型，二是部分过程或全过程的无菌操作3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal products 4 grades can be distinguished.无菌生产的洁净区，按照产品对环境的要求分级，每一步生产操作，在操作状态，对环境有相应的洁净级别的要求，以防止对所处理的材料或产品造成粉尘或微生物的污染。

为达到“动态”的条件，这些区域在设计上要达到“静态”的洁净标准静态”指设备已经安装并运行，生产设备就位但是没有操作人员在场动态”是指在设备正常运转状态下和有规定的工作人员在场的情况下每个或每套房间都要分别进行“静态”和“动态”的确定无菌产品的生产有4个环境级别：Grade A : The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean room applications.The maintenance of laminarity should be demonstrated and validated.A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.A级：用于高风险的生产操作，如灌装区、加盖区、容器开口区、和进行无菌连接的地方。

通常这种情况是带有层流罩的工作点在开放的洁净区内的工作点上，层流罩应该能产生风速为0.36 – 0.54米/秒的均匀气流层流罩的维护，必须有充分的证明和经过验证密封隔离箱和手套箱内，可采用单向低速气流Grade B : For aseptic preparation and filling, this is the background environment for the grade A zone.B级：对于无菌制备和灌装，B级区域是A级区域的背景环境Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.C级和D级：无菌产品非关键生产步骤的洁净区The airborne particulate classification for these grades is given in the following table:上述级别的环境的空气中尘埃粒子标准如下：Grade空气级别at rest (b) 静态（b）in operation (b) 动态(b)maximum permitted number of particles/m3 equal to or above (a)允许最大尘埃粒子数/m3 等于或大于(a)0.5μm(d)5μm0.5μm(d)5μmA35001（e）35001（e）B(C)35001（e）3500002000C(C)3500002000350000020000D(C)350000020000未规定(f)未规定(f)Notes注: a) Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B areas. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas.尘埃粒子检查。